Osteoporosis is a serious health concern of the elderly that is expected to become more prevalent as the US population ages. Like many complex physiological systems, bone biology is dependent on both genetic factors and environmental factors like diet. It is not clear, however, whether genetic and dietary factors are independent modifiers of bone health or whether their effects are synergistic. Our long-term goal is to identify the genetic variants that influence an individual's response to low dietary calcium intake and then use this information as a foundation for making personalized diet recommendations to optimize bone health. In the short term, we have two general gene x environment (GXE) interaction models that we will test. The first model predicts that the benefits of high bone mass genotypes require the presence of high dietary calcium intake to be realized (i.e. diet is permissive). The second model predicts that polymorphisms in genes controlling nutrient metabolism or utilization lead to individuals that are more sensitive to inadequate dietary calcium intake (i.e. the consequence of genotype is conditional). To address these models, and to identify genetic variation that influences the physiologic response to inadequate dietary calcium intake, we have developed three specific aims (SA): SA1: Test whether dietary Ca intake influences the ability of mice with the LRP5 G171V polymorphism to reach their genetic potential for high bone mass. LPR5 is essential for normal osteoblast development and the G171V mutation causes high bone mass. This will directly test the GXE model 1. SA2: Develop humanized mouse models to test whether the less active "f" allele of the FokI start codon polymorphism in the human (vitamin D receptor) VDR gene make these mice more sensitive to the negative impact of dietary calcium depletion on bone. The longer "f" form of the VDR is proposed to be less transcriptionally active than the shorter "F" allele and this would make mice humanized to have the "f'form less able to adapt to low calcium diets that increase serum 1,25 dihydroxyvitamin D levels (a major regulator of calcium metabolism). We will create mice humanized to have these two VDR isoforms so that we can use them in future proposals to directly test GXE model 2. SA3: To use forward genetics in the BXD recombinant inbred (RI) mouse panel to identify QTLs responsible for differential responses of bone and calcium metabolism to dietary calcium restriction. We will use the BXD RI panel to characterize the response of bone density and intestinal calcium absorption to dietary calcium restriction. These studies will identify QTLs that contain candidate gene polymorphisms that can be examined in future studies. Our lab is well positioned to conduct the research in these three aims due to its long history of mechanistic studies on the impact of dietary calcium on bone and mineral metabolism using mouse models. In addition, we have developed collaborations and associations that will permit us to conduct the careful analyses needed for these GXE studies. PUBLIC HEALTH RELEVANCE: Both inherited genetic factors and lifestyle habits like high dietary calcium intake are essential for optimal bone health and for the prevention of the bone disease osteoporosis. Some believe that osteoporosis prevention messages should be targeted to only those people whose genetics make them "at risk" for the disease, i.e. high dietary calcium intake may only benefit a subset of the US population. However, the relationship between dietary calcium intake and a person's genetic background isn't clear. Our research will examine this relationship in detail using animal models.